NM_004972.4:c.2571+2976T>A

Variant names:

• chr9-5084837-T-A
• rs6476939
• NM_004972.4:c.2571+2976T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004972.4(JAK2):​c.2571+2976T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 152,134 control chromosomes in the GnomAD database, including 30,398 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (30398 hom., cov: 33)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.699
• Publications: 11 publications found

Genes affected

JAK2 (HGNC:6192): (Janus kinase 2) This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

PDSS1P1 (HGNC:49740): (decaprenyl diphosphate synthase subunit 1 pseudogene 1)

INSL6 (HGNC:6089): (insulin like 6) The protein encoded by this gene contains a classical signature of the insulin superfamily and is significantly similar to relaxin and relaxin-like factor. This gene is preferentially expressed in testis. Its expression in testis is restricted to interstitial cells surrounding seminiferous tubules, which suggests a role in sperm development and fertilization. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.2571+2976T>A		intron_variant	Intron 19 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.2571+2976T>A		intron_variant	Intron 19 of 24	1	NM_004972.4	ENSP00000371067.4
PDSS1P1	ENST00000422953.1	n.*162A>T		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92516 AN: 152016 Hom.: 30351 Cov.: 33

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.584

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.609 AC: 92619 AN: 152134 Hom.: 30398 Cov.: 33 AF XY: 0.608 AC XY: 45202 AN XY: 74374

African (AFR) AF: 0.872 AC: 36229 AN: 41534

American (AMR) AF: 0.543 AC: 8307 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2028 AN: 3470

East Asian (EAS) AF: 0.448 AC: 2322 AN: 5186

South Asian (SAS) AF: 0.513 AC: 2476 AN: 4822

European-Finnish (FIN) AF: 0.555 AC: 5859 AN: 10554

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33477 AN: 67964

Other (OTH) AF: 0.586 AC: 1237 AN: 2112

Alfa AF: 0.570 Hom.: 3192

Bravo AF: 0.617

Asia WGS AF: 0.543 AC: 1886 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.83
PhyloP100		0.70
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6476939; hg19: chr9-5084837; COSMIC: COSV67570408;